To support the free and open dissemination of research findings and information on alcoholism and alcohol-related problems. To encourage open access to peer-reviewed articles free for all to view.

For full versions of posted research articles readers are encouraged to email requests for "electronic reprints" (text file, PDF files, FAX copies) to the corresponding or lead author, who is highlighted in the posting.


Monday, May 28, 2012

Blockade of the brain histamine H3 receptor by JNJ-39220675: preclinical PET studies with [11C] GSK189254 in anesthetized baboon

The preclinical characterization of a series of aryloxypyridine amides has identified JNJ-39220675 ((4- cyclobutyl-1,4-diazepan-1-yl)(6-(4-fluorophenoxy)pyridin-3-yl)methanone) as a high-affinity histamine H3 receptor antagonist and a candidate for further drug development
particularly in the treatment of alcohol-related behaviors.

This study measured brain histamine H3 receptor
blockade by JNJ-39220675 (1 mg/kg) in the female baboon.

Positron emission tomography imaging and [11C]

GSK189254, a reversible high-affinity radiotracer with specificity for the histamine H3 receptor, was used to measure histamine H3 receptor availability at baseline and after i.v. and oral administration of JNJ-39220675 (1 mg/kg) in
the anesthetized baboon. Histamine H3 receptor availability was estimated as the total distribution volume (VT) in brain regions. The sensitivity of [11C]GSK189254 binding to injected mass and carryover effects was determined.

JNJ-39220675 produces robust (ca. 90 %) blockade of [11C]GSK189254 binding after i.v. and oral administration. After oral administration of JNJ-39220675 (1 mg/kg), the fractional receptor occupancy was >0.9 at 90 min with a
slight increase from 90 to 240 min. Similar to prior studies in humans, VT was highly sensitive to the mass of GSK189254 with ED50 estimated to be 0.16 μg/kg.

The robust blockade of binding of [11C] GSK189254 by JNJ-39220675 demonstrates that this compound readily penetrates the blood–brain barrier and occupies the histamine H3 receptor after oral administration at low plasma concentrations (∼1 ng/cc) supporting further
drug development for alcohol addiction and other disorders.

This study corroborates prior reports of the high sensitivity of [11C]GSK189254 to injected mass at doses >0.1 μg/kg.

Read Full Text (PDF)